Our long-term objective is to establish the feasibility of ultrashort, high field electrical pulses as a mechanism of cardiac stimulation, contraction enhancement, and defibrillation. The major modes of death in heart failure are sudden cardiac death (SCD) and refractory pump failure. Ventricular fibrillation (VF) is the leading cause of SCD and can only be treated by defibrillation, which uses high voltage fields and succeeds at the cost of pain, discomfort and battery demands. Pump failure treatment with positive inotropic agents leads to hemodynamic improvements but causes long-term increased mortality. New strategies to defibrillate and enhance contraction are needed. Ultrashort (ns), high-field (MV/m), low energy (microJ) pulses have recently been shown to trigger a variety of cellular effects in nonexcitable cells, including calcium release from intracellular stores, poration of the nuclear membrane, translocation of phosphatidylserine from the inner to the outer layer of the plasma membrane, and induction of apoptosis. These responses are thought to be caused by the substantial intracellular electric fields generated, which are too brief to charge or irreversibly damage the plasma membrane, deemed to be "transparent" to the fields. Effects on excitable cells have not been systematically studied, but preliminary data suggests that ultra-short, high-field electric pulses can excite cardiac cells and potentially generate enhanced contraction with much lower energy use by. The first aim of this project is to delineate the physiological effects of nanosecond, megavolt-per-meter electric pulses in isolated rabbit myocytes. Systematic studies of pulse regimens vs. responses under different physiological conditions will be performed to delineate the voltage and calcium responses and their mechanisms. The second aim is to explore the effects of nanosecond, high-field pulses in cardiac impulse propagation in 2-dimensional cardiac substrates. We will first develop electrode configurations for delivery of megavolt nanosecond pulses to larger cardiac tissues. We will then study the effects of these pulses on impulse propagation in neonatal rat myocyte monolayers. Effects of pulses on paced, spiral wave and fibrillatory propagation will be assessed to establish their feasibility as an antifibrillatory strategy. If successful, our studies would provide a basis for a new, low energy technology for cardiac pacing, and defibrillation which could improve the quality of life and survival of millions of patients with heart failure. [unreadable] [unreadable] [unreadable]